Turning your cancer against itself

Turning Your Cancer Against Itself

Precision medicine has been sold as customizing treatments for patients, matching drugs to disease-causing genes that just a few thousand or even hundreds of patients carry.

Its boosters may have been underselling the concept: If a cutting-edge cancer treatment succeeds, it can be matched precisely to a single patient.

The experimental treatment, called a neoantigen vaccine, fires up the immune system to attack malignant cells. From the evidence so far, patients’ tumors — even if they are all diagnosed as melanoma, for example, or breast or lung, or colorectal cancer — are as unique as the pattern of freckles on the faces of a kindergarten-full of redheads. That means vaccines to treat them will also be unique.

Although not a single such therapeutic vaccine has yet been approved for use, promising results from small studies, plus the general sense that the immune system may be cancer’s most powerful foe, have led scientists from major cancer centers to launch clinical trials of these cancer vaccines and found companies to commercialize them. Investors are bullish enough on the approach to have put tens of millions of dollars into these startups, and established drug and biotech companies are racing to partner with them. The arrival of cheap, fast DNA sequencing has made individualized therapy practical, contributing to the explosion in interest.

Nevertheless, said Gregory Lizee of MD Anderson Cancer Center in Houston, “the jury is still out” on whether therapeutic cancer vaccines will live up to the soaring hopes. And some are already sounding cautions about their potential cost.

The annals of cancer research are full of brilliant ideas that failed, but neoantigen vaccines just might be an exception. After decades of futility, immune approaches to cancer have recently become surprise successes, with two immune-based drugs — including one that former president Jimmy Carter received for advanced melanoma — in use and others in the pipeline. And the immune approach is expected to be a focus of the cancer “moonshot” that Vice President Joe Biden has proposed.

The vaccines build on a rare phenomenon often called a medical miracle — cancers that melt away without treatment. In fact, such spontaneous remission reflects real biology: The immune system can eliminate cancer. For the nearly 600,000 Americans who died of cancer last year, that obviously didn’t happen. But neoantigen vaccines “can make it happen,” said Dr. Elizabeth Jaffee, deputy director of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. “The hope is that we can turn cancers from ones that don’t attract immune cells into those that do.”

For some 50 years, cancer biologists have tried to incite the immune system to attack cancer by targeting molecules that commonly stud the surfaces of malignant cells. These “antigens” act as homing beacons that immune cells find and lock onto (much as antigens on viruses attract the immune system, the basis for preventive vaccines such as that for measles).

Trouble is, normal cells sometimes sport the same antigens as tumors, and the immune system is programmed not to attack antigens found on healthy cells. As a result, revving up the immune system to target common tumor antigens hasn’t worked, leading to a number of failed experimental cancer vaccines.

That led biologists to a different approach: siccing the immune system on antigens found only on cancer cells — and only on the cancer cells of a single patient. “It’s highly unlikely that any two patients have the same neoantigens,” said Dr. Catherine Wu of Boston’s Dana-Farber Cancer Institute. “That’s why we have an opportunity to make cancer vaccines truly personalized, loaded with patient-specific neoantigens.”

To do that, scientists first collect bits of the tumor via biopsy. They sequence its DNA and the DNA of healthy cells, identifying differences between them. The differences are mutations; depending on the type of cancer, there can be a few dozen or (as in melanoma) even 1,000.

Next, they use algorithms to identify which mutated genes make antigens, rather than proteins that stay inside cells. About 3 to 5 out of 100 mutations make antigens, estimated Lizee. Many of them exist only in a single patient, and only on the tumor cells — hence the prefix “neo,” for new. Because they aren’t found on healthy cells, to the immune system they look like the biological equivalent of big neon signs flashing, “CANCER CELL RIGHT HERE!”

The antigens are then synthesized in the lab and packed into a vaccine, along with components called adjuvants that turbocharge the immune system. Although it takes only one neoantigen to attract tumor-destroying T cells, Wu and other experts believe that 20 would maximize the odds that a vaccine would work.

Producing a new vaccine for every cancer patient may sound impractical, not to mention wildly expensive. But scientists argue it needn’t be. The cost of sequencing a cancer cell’s genome — or at least the protein- and antigen-making part — has fallen from millions of dollars in the 2000s to $2,000 to $4,000 now, said immunologist Robert Schreiber of Washington University School of Medicine in St. Louis. The whole process, from sequencing to vaccine production, should take eight to 10 weeks and cost about $60,000, he estimates. In fact, one neoantigen start-up — Gritstone Oncology of San Francisco — has said the entire process of sequencing a patient’s tumor and making an individual vaccine will take it no more than a month.

A payer’s nightmare is a manufacturer’s dream. The prospect of true cancer cures and the high price that would command has lured a lengthening list of companies into the neoantigen field.

Last year alone saw the launch of Gritstone, with $102 million in private financing, as well as Neon Therapeutics in Cambridge, Mass., which raised $55 million and was cofounded by Wu, Schreiber, and other leading researchers. In November, Paris-based pharmaceutical giant Sanofi said it would partner with the private BioNTech of Mainz, Germany, to develop neoantigen vaccines.

Clinical trials are well underway. In one small study, all three patients with advanced melanoma had a strong immune response to a custom-made neoantigen vaccine that contained seven unique neoantigens, scientists led by Gerald Linette of Washington University’s Siteman Cancer Centerreported in Science last April; in two, the tumors shrank or stopped growing. Because the patients received other therapies, however, it’s not possible to credit the neoantigen vaccine with their improvement.

Siteman is planning to test neoantigen vaccines against melanoma,glioblastoma, triple-negative breast cancer, follicular cancer, and non-small cell lung cancer. Gritstone expects to begin testing neoantigen vaccines against lung cancer within the year, and at MD Anderson, Lizee is helping to identify antigens that will be used to vaccinate about 25 patients with pancreatic or colorectal cancer in a study beginning this year.

At Dana-Farber, researchers are running one clinical trial using Neon’s neoantigen vaccines against melanoma and another against glioblastoma. The melanoma patients receive a series of vaccine injections spread over 16 weeks, and the glioblastoma patients get five injections in the first three weeks and then two more later.

One patient in the trial, Marie, suffered a headache so intense three years ago that, as in every hypochondriac’s nightmare, turned out to be glioblastoma, a highly aggressive brain cancer with an abysmal prognosis. “I was willing to try anything,” said the 49-year-old real estate agent, wife, and mother of two. She has received multiple injections, but neither she nor the study’s doctors know whether they were vaccine or dummy shots. “But I’m running, I’m working, and I feel blessed,” she said. Her MRIs still show that she is cancer-free.

Neoantigen vaccines could turn out to be so much false hope, as too many other cancer treatments have. Or they might be Biden’s “moonshot,” especially if paired with the first generation of immune-based cancer drugs.

Merck’s Keytruda (which Carter received) and Bristol-Myer Squibb’s Opdivo and Yervoy remove biological blockades that keep T cells, a kind of immune cell, from attacking cancer. But they’re effective against only 20 percent of cancers, said Hopkins’ Jaffee. Other cancers don’t attract enough T cells, and some patients can’t mount an immune attack on their own. Neoantigen vaccines might raise the AWOL immune soldiers — while the blockade-removing drugs would let the cells swarm tumors like an army pouring over downed ramparts.

With that in mind, Neon announced a collaboration with Bristol-Myer Squibb to test Opdivo in combination with Neon’s experimental neoantigen vaccines for melanoma, non-small cell lung cancer, and bladder cancer.

Of course, cancer has thwarted many promising therapies. With neoantigen vaccines, tumors might mutate so they stop producing the antigens targeted by the vaccine.

“That’s a concern,” Wu said. “If you keep hitting and hitting the tumor cells with the immune system, they’ll find some way to get around that.” But by raising an immune army that targets 20 or so neoantigens, she said, that might be harder.

“If you target multiple mutations,” said Hopkins’ Jaffee, “hopefully the tumor isn’t smart enough to escape them all at once.”

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